title: Enhanced efficacy of therapeutic cancer vaccines produced by co-treatment with Mycobacterium tuberculosis heparin-binding hemagglutinin, a novel TLR4 agonist.
abstract: Effective activation of dendritic cells (DCs) toward T helper (Th)-1 cell polarization would improve DC-based antitumor immunotherapy, helping promote the development of immunotherapeutic vaccines based on T-cell immunity. To achieve this goal, it is essential to develop effective immune adjuvants that can induce powerful Th1 cell immune responses. The pathogenic organism Mycobacterium tuberculosis includes certain constitutes, such as heparin-binding hemagglutinin (HBHA), that possess a strong immunostimulatory potential. In this study, we report the first clarification of the functions and precise mechanism of HBHA in immune stimulation settings relevant to cancer. HBHA induced DC maturation in a TLR4-dependent manner, elevating expression of the surface molecules CD40, CD80, and CD86, MHC classes I and II and the proinflammatory cytokines IL-6, IL-12, IL-1β, TNF-α, and CCR7, as well as stimulating the migratory capacity of DCs in vitro and in vivo. Mechanistic investigations established that MyD88 and TRIF signaling pathways downstream of TLR4 mediated secretion of HBHA-induced proinflammatory cytokines. HBHA-treated DCs activated naïve T cells, polarized CD4(+) and CD8(+) T cells to secrete IFN-γ, and induced T-cell-mediated cytotoxicity. Notably, systemic administration of DCs that were HBHA-treated and OVA(251-264)-pulsed ex vivo greatly strengthened immune priming in vivo, inducing a dramatic regression of tumor growth associated with long-term survival in a murine E.G7 thymoma model. Together, our findings highlight HBHA as an immune adjuvant that favors Th1 polarization and DC function for potential applications in DC-based antitumor immunotherapy.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Pusan National University, Beom-eo Ri, Mulgum Eop, Yangsan, Gyeongsangnam-do, Republic of Korea.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Jeong
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Noh
authors.forename: Deok Rim
authors.initials: DR
authors.lastname: Heo
authors.forename: Yong Kyoo
authors.initials: YK
authors.lastname: Shin
authors.forename: Cheol-Heui
authors.initials: CH
authors.lastname: Yun
authors.forename: Won-Jung
authors.initials: WJ
authors.lastname: Koh
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Jake
authors.initials: J
authors.lastname: Whang
authors.forename: Hwa-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Won Sun
authors.initials: WS
authors.lastname: Park
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004357:Drug Synergism; D037102:Lectins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013945:Thymoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D019496:Cancer Vaccines; D037102:Lectins; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C104578:heparin-binding hemagglutinin